1. Field of the Invention
The present invention is in the field of pharmacotherapy of cognitive deficits in learning and memory by administering a nicotine antagonist alone, particularly mecamylamine. Examples of disorders associated with deficits in learning and memory are schizophrenia, bipolar disorder, obsessive compulsive disorder, attention deficit hyperactivity disorder, Alzheimer's Disease, and disorders of learning in children, adolescents and adults.
2. Background Information
Neuropsychological cognitive deficits in learning and memory are common in people with neuropsychiatric disorders (REF). For example, memory function is an important, but under-researched area for neuropsychological investigation in persons with bipolar disorder. Previous studies have reported cognitive deficits on tasks of declarative memory in bipolar patients in the euthymic state. Memory is more typically described as primary or immediate verbal memory and secondary verbal memory. Immediate memory is equivalent to short-term storage or information and is assessed with measures such as the Digit Span. This type of memory is not usually affected in amnesic patients. Secondary memory is memory for lists of words or stories, and it is often assessed after a time delay and is dysfunctional in amnesia. Card sorting refers to performance on the Wisconsin Card Sorting Test, which is considered a measure of executive functioning, concept formation, cognitive flexibility. Another aspect that is prominent in schizophrenia is the attentional deficit or lack of vigilance. Vigilance is often measured by a continuous performance test in which the subject is instructed to press a button in response to a specific target (a letter or number) but not other letters or numbers. This shows the ability to discriminate targets from nontargets (signal from noise).
Baddeley's model divides working memory into three components: a central executive that can manipulate information and two “slave” systems (one an articulatory loop for maintenance of verbal information and a visuospatial scratch pad for spatial information) (Baddeley A D. Science 255: 556–9, 1992). Verbal working memory refers to the integrity of the articulatory loop—the type of memory that is used to accurately retain a new telephone number long enough to make the call and that is essential for skill acquisition.
The changing scheme of drug reimbursement is forcing researchers to focus on the new drug's ability to help patients to function better in society. Previously successful treatment of schizophrenics was based on the abatement of the psychotic symptoms, such as hallucinations. The detrimental effects of schizophrenia on cognition have been recognized since the late 1800's. Emil Kraeplin originally coined the term “dementia praecox” occurring in a subset of patients with schizophrenia who experience, in addition to their chronic psychotic symptomatology, an ongoing dementing illness. The illness leads to progressive loss of IQ score, attention and memory loss. Recent studies with schizophrenic patients suggest that neuropsychological deficits in cognitive function contribute more to these patients' disability than do their symptoms of hallucinations and delusions.
Green (Am J Psychiatry 153(3): 321–330, 1996) reviewed many studies of schizophrenic rehabilitation and the correlation of rehabilitation with different symptoms, signs, and test results. He reviewed 1) studies that prospectively evaluated specific aspects of neurocognitive and community (e.g., social and vocational) functioning (six studies), 2) all known studies of neurocognitive correlates of social problem solving (five studies), and 3) all known studies of the neurocognitive correlates and predictors of psychosocial skill acquisition (six studies). Despite wide variation among studies in the selection of neurocognitive measures, some consistencies emerged. The most consistent finding was that verbal memory was associated with all types of functional outcome. Vigilance was related to social problem solving and skill acquisition. Card sorting (an indicator of executive function) predicted community functioning but not social problem solving. Negative symptoms (i.e., withdrawal) were associated with social problem solving but not skill acquisition. Notably, psychotic symptoms were not significantly associated with outcome measures in any of the studies reviewed.
Studies are beginning to focus on schizophrenia's effects on brain function and cognition. Recent clinical studies with newer atypical antipsychotics, such as risperidone, suggest that these drugs improve verbal working memory in schizophrenics; whereas, other drugs such as haloperidol do not (Green M F, Marshall B D, et al. Am J Psychiatry 154: 799–804, 1997). The authors posited that the beneficial effect of the newer antipsychotics was due to antagonistic action on the 5-hydroxytryptophan (5-HT2A) receptor. Conventional neuroleptics have primary affinity for the dopamine (D2) receptor and not 5-HT2A receptor.
Tourette's syndrome (TS) is an autosomal dominant neuropsychiatric disorder characterized by a range of symptoms, including multiple motor and phonic tics. Many TS patients also exhibit other neuropsychiatric abnormalities including obsessive compulsive symptoms (Pauls D L et al. Psychopharm Bull, 22: 730–733, 1986), hyperactivity and attention deficits (Comings D E, Himes J A, Comings B G, J Clin Psychiatry, 51: 463–469, 1990). Problems with extreme temper or aggressive behavior also are frequent (Riddle M A et al. WILEY SERIES IN CHILD AND ADOLESCENT MENTAL HEALTH, Eds. Cohen D J, Bruun, R D, Leckman J F, New York City, John Wiley and Sons, pp. 151–162, 1988; Stelf M E, Bornstein R A, Hammond L, A survey of Tourette syndrome patients and their families: the 1987 Ohio Tourette Survey, Cincinnati, Ohio Tourette Syndrome Association, 1988), as are learning disabilities (Harris D, Silver A A, Learning Disabilities, 6(1): 1–7, 1995; Silver A A, Hagin R A, DISORDERS OF LEARNING CHILDHOOD, New York City: Wiley, pp. 469–508, 1990).
Erenberg et al. (Erenberg G, Cruse R P, Rothner A D, Ann Neurol 22: 383–385, 1987) found that most patients with TS stopped neuroleptic medications by age 16, often because of side effects such as tardive dyskinesia. Many older, non-medicated TS patients are disqualified for full-time, responsible jobs.
It has been observed that 50% of children presenting with TS also have Attention Deficit Hyperactivity Disorder (ADHD). ADHD is a neurobiological disorder characterized by impaired attentiveness, increased impulsivity, and hyperactivity. ADHD is now the most commonly diagnosed childhood psychiatric condition, with some 3.5 million children afflicted. In addition, 60% of adolescents with ADHD continue to have symptoms in adulthood, representing another 2.5 million patients.
Added to the fourth edition Diagnostic and Statistical Manual of Mental Disorders was executive dysfunction, or an individual's inability to organize and effectively carry out nonroutine, goal-directed behaviors, and include problems in goal selection, planning, behavioral sequencing, judgment, working memory, and attention. This diagnosis cuts across traditional diagnostic boundaries. It occurs in both cortical and subcortical dementias, schizophrenia, affective disorders, traumatic brain injury and many other neuropsychiatric and neurological disorders. No one single test such as card sorting can adequately measure its impairment. However, executive dysfunction can be determined by a skillful history, functional impairments, and clinical observation. Attempts to treat executive dysfunction with medication have met with limited success (Mahurin R K, Sem in Clin Neuropsychiatry 4(1): 2–4, 1999).
Obsessive compulsive disorder (OCD) is associated with specific cognitive deficits on tasks of executive and visual memory function (Purcell R et al. Biol Psychiatry 43(5): 348–57, 1998). When Tourette's syndrome was combined with OCD or attention deficit symptoms, impaired achievement and execution functioning were correlated with obsessive and obsessive/attention symptoms, but not with attention symptoms alone (De Groot C M et al. J Neuropsychiatry Clin Neurosci 9(2): 267–72, 1997).
The current patent application is concerned with the administration of nicotine antagonists, particularly mecamylamine (3-methylamino-2,2,3-trimethylnorcamphane). Mecamylamine is well known as a nicotine antagonist and blocks ganglia which nicotine stimulates. First introduced as an anti-hypertensive, mecamylamine blocks sympathetic ganglia transmission and thereby causes vasodilatation and a fall in blood pressure (Taylor P, In: Goodman L S, Gilman A (eds) The Pharmacological Basis of Therapeutics, McMillan Publishing Co., New York City, pp. 193–95, 1996). Generalized ganglionic blockade may result also in atony of the bladder and gastrointestinal tract, impaired sexual function, cycloplegia, xerostomia, diminished perspiration and postural hypotension. While the clinical use of mecamylamine as a ganglionic agent has largely been replaced by more effective antihypertensive medications, scientists remain interested in mecamylamine because of its ability to block nicotine binding sites in the brain (see, e.g., Martin B R, Onaivi E S, Martin T J, Biochemical Pharmacology 38: 3391–3397, 1989; and Banerjee S et al, Biochemical Pharmacology 40(9): 2105–2110, 1990). These nicotine binding sites, known as nicotinic acetylcholinergic receptors (nAChr), are normally activated in the brain by acetylcholine, a prominent neurotransmitter. Mecamylamine's amnesic effects have been well documented (Rush D K, Streit K. Psychopharmacology (Berl) 106: 375–82, 1992; Elrod K, Buccafusco J J. J Pharmacol Exp Ther 258: 403–9, 1991).
Unlike some ganglionic blocking agents, which do not readily reach the central nervous system (CNS), mecamylamine has been reported to produce central effects in humans, such as blocking the CNS actions of nicotine (Martin B R, Onaivi E S, Martin T J, Biochemical Pharmacology 38: 3391–3397, 1989) and in altering cognitive functioning (Newhouse Pa. et al, Neuropsychopharmacology 10: 93–107, 1994), electrical brain waves (Pickworth W B, Heming R I, Henningfield J E, Pharmacology Biochemistry & Behavior 30: 149–153, 1988) and cortical blood flow (Gitalman D R, Prohovnik I, Neurobiology of Aging 13: 313–318, 1992).
In a recent study of the nicotine receptor (nicotine binding site) and its ion channel (mecamylamine binding site), Banerjee et al. disclosed that mecamylamine and several nicotine analogs have a high affinity for the mecamylamine site. Like mecamylamine, several nicotine analogs also have anti-nicotinic effects (Banerjee S et al. Biochem Pharmacol 40(9): 2105–10, 1990). Research is also proceeding on alkaloids which act on the nicotinic receptor channels (Daly J W: Alkaloids as Agonists, Antagonists and Noncompetitive Blockers of Nicotinic Receptor Channels. In: Proceedings of Nicotinic Acetylcholine Receptors as Pharmaceutical Targets. Jul. 24–25, 1997, Washington, D.C.).
Nicotine, via tobacco in various forms, has been one of the most widely utilized drugs for centuries (Wilbert J, J Ethnopharmacol 32(1–3): 179–186, 1991). Nicotine is a potent modulator of nAChrs (Changeux J P, Sci Amer (November) pp. 58–62, 1993). Through these receptors, nicotine activates the presynaptic release of several neurotransmitters including acetylcholine, norepinephrine, serotonin and dopamine (Balfour DJK, Pharmacological Therapeutics 16: 269–282, 1982). Agents which can modulate central monoaminergic neurotransmissions by acting on nAChrs may be useful therapeutically for treating neuropsychiatric disorders (Jarvick M E, Br J Addict 86: 571–575, 1991; Newhouse Pa., Hughes J R. Br J Addict 86: 521–526, 1991; and Hughes J, Clarke PBS (Eds): The effects of nicotine on biological systems II. Abstract S40, 1994; Decker MW et al, Life Sci 56: 545–570, 1995). Nicotine has been shown to improve cognitive performance (Wesnes K, Parrott A. SMOKING, NICOTINE AND HUMAN PERFORMANCE. HANDBOOK OF HUMAN PERFORMANCE. London, Academic Press, 1992. pp 127–67)
U.S. Pat. No. 5,774,052 to Rose and Levin discloses agonist-antagonist combinations to reduce the use of nicotine and other drugs. In combination with nicotine, the nicotinic antagonist mecamylamine was given to treat tobacco dependency. Rose and Levin proposed including both nicotine and mecamylamine in a patch. Rose and Levin also suggested that such agonist-antagonist combinations could be used in other psychopathological disorders and cases involving neuronal dysfunction (e.g., manic depression, schizophrenia and hypertension due to sympathetic autonomic disorder).
It would benefit patients to be able to have better symptom control and fewer side effects. In particular, it would be preferable to take a single drug to improve cognition and societal functioning, as did patients in at least some of the reports disclosed herein. Our clinical experience with mecamylamine in human patients with a variety of diagnoses supports use in improving cognition. Based on our experience with patients with Tourette's Syndrome, bipolar disorder, ADHD, and schizophrenia-like symptoms, persons with neuropsychological cognitive deficits in learning and memory are also likely to benefits from treatment with mecamylamine and other nicotine antagonists.